This artistic research reflection explores Sweden’s legally-mandated ‘tourist-release’ at the Ångermanälven River’s storied site of Nämforsen. Against World Wars and calls for energy independence of ...the mid 1940s, the iconic Ångermanälven River was industrialised from a free-flowing salmon river to eventually a series of 44 dams and hydropower plants. Later, a unique environmental court legal judgement resulted in ‘tourist-water’ at Nämforsen that gives the illusion of a free-flowing river during summer months. Existing for solely aesthetic purposes, tourist-water is an unexplored example of the (in)visible powers perpetuating myths associated with hydropower and place in Sweden. Through text and images, this piece reflects on witnessing this tourist-water phenomena through place-based documentary arts practice. The fieldwork is part of a doctoral project in artistic practice focusing on how photography can mediate complex issues in places of environmental change through the case of Nämforsen. Strategies such as framing, time-scaling and montage have emerged from this practice at the same time as ethical concerns related to representation are raised. This case is especially pertinent as hydropower in Sweden comes under increased scrutiny, simultaneously as it is marketed as a sustainable energy solution. The piece furthermore highlights the lasting implications of conservation efforts centred historically on aesthetic rather than ecologic values.
H3N2 influenza viruses have now circulated in the human population for 43 years since the pandemic of 1968, accumulating sequence changes in the hemagglutinin (HA) and neuraminidase (NA) that are ...believed to be predominantly due to selection for escape from antibodies. Examination of mutations that persist and accumulate led to identification of antigenically significant mutations that are contained in five antigenic sites (A-E) mapped on to the H3 HA. In early H3N2 isolates, antigenic site A appeared to be dominant while in the 1990s site B seemed more important. To obtain experimental evidence for dominance of antigenic sites on modern H3 HAs, we have measured antibodies in plasma of human subjects who received the 2006-07 trivalent subunit influenza vaccine (H3 component A/Wisconsin/67/05) or the 2008-09 formulation (H3 component A/Uruguay/716/07). Plasmas were tested against expressed HA of Wisconsin-like influenza A/Oklahoma/309/06 and site-directed mutants in antigenic site A (NNES121-124ITEG, N126T, N133D, TSSS135-138GSNA, K140I, RSNNS142-146PGSG), and antigenic site B (HL156-157KS, KFK158-160GST, NDQI189-192QEQT, A196V). "Native ELISA" analysis and escape mutant selection with two human monoclonal antibodies demonstrated that antibody E05 binds to antigenic site A and 1_C02 binds to site B. We find that most individuals, after vaccination in seasons 2006-07 and/or 2008-09, showed dominance of antigenic site B recognition over antigenic site A. A minority showed dominance of site A in 2006 but these were reduced in 2008 when the vaccine virus had a site A mutation. A better understanding of immunodominance may allow prediction of future antigenic drift and assist in vaccine strain selection.
CD73 is overexpressed in many types of human and mouse cancers and is implicated in the control of tumor progression. However, the specific contribution from tumor or host CD73 expression to tumor ...growth remains unknown to date. Here, we show that host CD73 promotes tumor growth in a T cell-dependent manner and that the optimal antitumor effect of CD73 blockade requires inhibiting both tumor and host CD73. Notably, enzymatic activity of CD73 on nonhematopoietic cells limited tumor-infiltrating T cells by controlling antitumor T cell homing to tumors in multiple mouse tumor models. In contrast, CD73 on hematopoietic cells (including CD4⁺CD25⁺ Tregs) inhibited systemic antitumor T cell expansion and effector functions. Thus, CD73 on hematopoietic and nonhematopoietic cells has distinct adenosinergic effects in regulating systemic and local antitumor T cell responses. Importantly, pharmacological blockade of CD73 using its selective inhibitor or an anti-CD73 mAb inhibited tumor growth and completely restored efficacy of adoptive T cell therapy in mice. These findings suggest that both tumor and host CD73 cooperatively protect tumors from incoming antitumor T cells and show the potential of targeting CD73 as a cancer immunotherapy strategy.
Glioblastoma (GB) is one of the deadliest brain cancers to afflict humans, and it has a very poor survival rate even with treatment. The extracellular adenosine-generating enzyme CD73 is involved in ...many cellular functions that can be usurped by tumors, including cell adhesion, proliferation, invasion, and angiogenesis. We set out to determine the role of CD73 in GB pathogenesis. To do this, we established a unique GB mouse model (CD73-FLK) in which we spatially expressed CD73 on endothelial cells in CD73−/− mice. This allowed us to elucidate the mechanism of host CD73 versus GB-expressed CD73 by comparing GB pathogenesis in WT, CD73−/−, and CD73-FLK mice. GB in CD73−/− mice had decreased tumor size, decreased tumor vessel density, and reduced tumor invasiveness compared with GB in WT mice. Interestingly, GBs in CD73-FLK mice were much more invasive and caused complete distortion of the brain morphology. We showed a 20-fold upregulation of A2B AR on GB compared with sham, and its activation induced matrix metalloproteinase-2, which enhanced GB pathogenesis. Inhibition of A2B AR signaling decreased multidrug resistance transporter protein expression, including permeability glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). Further, we showed that blockade of A2B AR signaling potently increased GB cell death induced by the chemotherapeutic drug temozolomide. Together, these findings suggest that CD73 and A2B AR play a multifaceted role in GB pathogenesis and progression and that targeting the CD73–A2B AR axis can benefit GB patients and inform new approaches for therapy to treat GB patients.
Recent studies have reported that adenosine is a significant mediator of regulatory T cell (Treg) function. Indeed, activation of the adenosine receptor subtypes expressed by a broad range of immune ...and inflammatory cells attenuates inflammation in several disease models. This anti-inflammatory response is associated with an increase in intracellular cAMP that inhibits cytokine responses of many immune/inflammatory cells, including T cells and APCs. Thus, adenosine produced by Tregs can provide a paracrine feedback that shapes the host response following an immunologic provocation. This review discusses the evidence that adenosine is an integral part of Treg biology and presents some of the mechanisms that may account for its contribution to the resolution of inflammation and the regulation of the immune/inflammatory cell phenotype.
Extracellular adenosine has been implicated in adaptation to hypoxia and previous studies demonstrated a central role in vascular responses. Here, we examined the contribution of individual adenosine ...receptors (ARs: A1AR/A2AAR/A2BAR/A3AR) to vascular leak induced by hypoxia. Initial profiling studies revealed that siRNA-mediated repression of the A2BAR selectively increased endothelial leak in response to hypoxia in vitro. In parallel, vascular permeability was significantly increased in vascular organs of A2BAR−/−-mice subjected to ambient hypoxia (8% oxygen, 4 hours; eg, lung: 2.1 ± 0.12-fold increase). By contrast, hypoxia-induced vascular leak was not accentuated in A1AR−/−-, A2AAR−/−-, or A3AR−/−-deficient mice, suggesting a degree of specificity for the A2BAR. Further studies in wild type mice revealed that the selective A2BAR antagonist PSB1115 resulted in profound increases in hypoxia-associated vascular leakage while A2BAR agonist (BAY60-6583 2-6-amino-3,5-dicyano-4-4-(cyclopropylmethoxy)-. phenylpyridin-2-ylsulfanylacetamide) treatment was associated with almost complete reversal of hypoxia-induced vascular leakage (eg, lung: 2.0 ± 0.21-fold reduction). Studies in bone marrow chimeric A2BAR mice suggested a predominant role of vascular A2BARs in this response, while hypoxia-associated increases in tissue neutrophils were, at least in part, mediated by A2BAR expressing hematopoietic cells. Taken together, these studies provide pharmacologic and genetic evidence for vascular A2BAR signaling as central control point of hypoxia-associated vascular leak.
In aluminosilicate glasses, recent experimental work has greatly increased our knowledge of structural details that go beyond conventional models, such as high-coordinated Al and non-bridging oxygens ...(NBO) in metaluminous and even peraluminous compositions. Particularly as network cation coordination increases at high pressure, the interplay of such species (how their concentrations depend on each other through reaction equilibria) becomes especially important to understand and to relate to physical properties: for example, in NBO-rich compositions, this species is systematically reduced as Al or Si coordination increases. These interactions can often be seen more clearly in ambient-pressure borosilicate and germanate systems, where composition and temperature can have dramatic effects on network and oxygen speciation. In particular, the field strengths of the network modifier cations have strong effects on structure, as higher field strength often promotes the concentration of negative network charge as either NBO or highly-charged BO such as Al–O–Al groups; accompanying changes in network cation coordination often occur but are linked in a complex fashion. Here we compare such speciation reactions in silicate, aluminosilicate, borosilicate and germanate melt systems, primarily as sampled by high-resolution NMR spectroscopy, note commonality of behavior, and point out important gaps in our knowledge for future exploration.
► Non-bridging oxygens interact in complex ways with network cation coordination ► Changes with pressure, temperature and composition reveals these interactions ► Structural inferences can be transferred among silicate, borate, germanate systems ► Modifier cation field strength has major and systematic effects on structure ► A simple notation allows correct mass and charge balancing of speciation reactions
CD73, originally defined as a lymphocyte differentiation antigen, is thought to function as a cosignaling molecule on T lymphocytes and an adhesion molecule that is required for lymphocyte binding to ...endothelium. We show here that CD73 is widely expressed on many tumor cell lines and is upregulated in cancerous tissues. Because the ecto-5'-nucleotidase activity of CD73 catalyzes AMP breakdown to immunosuppressive adenosine, we hypothesized that CD73-generated adenosine prevents tumor destruction by inhibiting antitumor immunity. We confirmed this hypothesis by showing that combining tumor CD73 knockdown and tumor-specific T-cell transfer cured all tumor-bearing mice. In striking contrast, there was no therapeutic benefit of adoptive T-cell immunotherapy in mice bearing tumors without CD73 knockdown. Moreover, blockade of the A2A adenosine receptor with a selective antagonist also augmented the efficacy of adoptive T-cell therapy. These findings identify a potential mechanism for CD73-mediated tumor immune evasion and point to a novel cancer immunotherapy strategy by targeting the enzymatic activity of tumor CD73.
The greatest contributors to cancer mortality are metastasis and the consequences of its treatment. Here, we present a novel treatment of metastatic breast cancer that combines photothermal therapy ...with targeted single-walled carbon nanotubes (SWCNTs) and immunostimulation with a checkpoint inhibitor. We find that the selective near-infrared photothermal ablation of primary orthotopic EMT6 breast tumors in syngeneic BALB/cJ mice using an annexin A5 (ANXA5) functionalized SWCNT bioconjugate synergistically enhances an anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4)-dependent abscopal response, resulting in an increased survival (55%) at 100 days after tumor inoculation. In comparison, there was no survival at 100 days for either photothermal therapy by itself or immunostimulation by itself. Prior to photothermal therapy, the SWCNT-ANXA5 bioconjugate was administered systemically at a relatively low dose of 1.2 mg/kg, where it then accumulated in tumor vasculature via ANXA5-dependent binding. During photothermal therapy, the average maximum temperature in the tumor reached 54 °C (duration 175 s). The mechanism of prolonged survival resulting from combinatorial photothermal ablation and immune stimulation was evaluated by flow cytometric quantification of splenic antitumoral immune effector cells and serum cytokine quantification.
Objective
Systemic lupus erythematosus (SLE) is a multifaceted disease characterized by immune dysregulation and unpredictable disease activity. This study sought to evaluate the changes in plasma ...concentrations of soluble mediators that precede clinically defined disease flares.
Methods
Fifty‐two different soluble mediators, including cytokines, chemokines, and soluble receptors, were examined using validated multiplex bead‐based or enzyme‐linked immunosorbent assays in plasma from 28 European American patients with SLE who developed disease flare 6 or 12 weeks after a baseline assessment (preflare), 28 matched SLE patients without impending flare (nonflare), and 28 matched healthy controls. In a subset of 13 SLE patients, mediators within samples obtained preceding disease flare were compared with those within samples from the same individual obtained during a clinically stable period without flare.
Results
Compared to SLE patients with clinically stable disease, SLE patients with impending flare had significant alterations (P ≤ 0.01) in the levels of 27 soluble mediators at baseline; specifically, the levels of proinflammatory mediators, including Th1‐, Th2‐, and Th17‐type cytokines, were significantly higher several weeks before clinical flare. Baseline levels of regulatory cytokines, including interleukin‐10 and transforming growth factor β, were higher in nonflare SLE patients, whereas baseline levels of soluble tumor necrosis factor receptor type I (TNFRI), TNFRII, Fas, FasL, and CD40L were significantly higher (P ≤ 0.002) in preflare SLE patients. The normalized and weighted combined soluble mediator score was significantly higher (P ≤ 0.0002) in preflare samples from SLE patients compared to samples from the same patients obtained during periods of stable disease.
Conclusion
The levels of proinflammatory adaptive cytokines and shed TNF receptors are elevated prior to disease flare, while the levels of regulatory mediators are elevated during periods of stable disease. Alterations in the balance between inflammatory and regulatory mediators may help identify patients at risk of disease flare and help decipher the pathogenic mechanisms of SLE.
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